Overexpression of the nuclear transport protein Nup88 is a common feature of many cancers. Additionally, the extent to which Nup88 is overexpressed within a given tumor has been extensively linked with tumor aggressiveness and reduced patient survival. However, the extent to which Nup88 overexpression contributes to cellular transformation and cancer pathogenesis is unknown. Because several components of the nuclear transport machinery have been implicated in regulating chromosome segregation, perturbation of Nup88 could simultaneously activate multiple oncogenic pathways during interphase and mitosis. The critical barrier to testing this novel idea has been the lack of a genetic model that recapitulates human physiology. We removed this barrier by generating a transgenic mouse model that broadly overexpresses Nup88. Using this and other mouse models, we will determine whether and how Nup88 overexpression drives multistage tumorigenesis. To achieve this objective, we will test our central hypothesis that Nup88 overexpression promotes tumor growth and metastasis through chromosomal instability and defective nuclear-cytoplasmic transport. To test this hypothesis, we will pursue three specific aims. In the first aim, we will determine the extent to which Nup88 overexpression promotes tumor growth and metastasis in vivo. In the second aim, we will elucidate the molecular mechanisms by which Nup88 overexpression drives chromosomal instability. In the third aim, we will establish the consequences of Nup88 overexpression on nuclear transport and subcellular distribution of cancer-critical tumor promoters and tumor suppressors. The long-term goal of our research is to exploit defective nuclear transport machinery, like Nup88, as novel therapeutic targets for the treatment of human cancers. The overall impact of this project is that the proposed research will enhance our general understanding of cancer pathophysiology, particularly as it relates to the deregulation of nuclear-cytoplasmic transport and chromosome segregation, and it will identify Nup88 as a promising novel therapeutic target for the treatment of several human cancers.